ARS-853

製品コードS8156 バッチS815603

化学情報

	Synonyms	N/A	Storage (From the date of receipt)	3 years -20°C powder 1 years -80°C in solvent
	化学式	C₂₂H₂₉ClN₄O₃
	分子量	432.94	CAS No.	1629268-00-3
Solubility (25°C)*	体外	DMSO	86 mg/mL warmed with 50ºC water bath (198.64 mM)
		Ethanol	7 mg/mL warmed with 50ºC water bath (16.16 mM)
		Water	Insoluble
* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

溶剤液（一定の濃度）を調合する

生物活性

製品説明	ARS-853 is a selective, covalent KRAS(G12C) inhibitor that inhibits mutant KRAS-driven signaling by binding to the GDP-bound oncoprotein and preventing activation. ARS-853 also induces apoptosis.
in vitro	ARS-853 treatment of KRAS^G12C cells led to a dose-dependent and nearly complete inhibition of CRAF-RBD (RBD)-mediated pulldown of KRAS from lysates, with an IC50 of approximately 1 μmol/L. Treatment of H358 cells by ARS-853 resulted in a significant loss of KRAS–CRAF interactions. Consistent with an inactive state of KRAS^G12C once bound to ARS-853, downstream signaling through both MAPK (including pMEK, pERK, and pRSK) and PI3K signaling (pAKT) pathways was inhibited by ARS-853 in H358 and other KRAS^G12C cell lines. The inhibition of RAF-RBD pulldown and KRAS downstream signaling was sustained over a period of 72 hours, accompanied by G1 cell-cycle arrest, loss of Cyclin D1 and Rb expression, and an increase in the cell-cycle inhibitor p27 KIP1. In addition, hallmarks of apoptosis, including cleaved PARP and increases in sub-diploid DNA, were observed in H358 cells following treatment with ARS-853. No effects on RAF-RBD binding or downstream signaling were observed in A549 cells (KRASG12S), and the inhibitory effects of ARS-853 in H358 cells could be rescued by ectopic expression of KRAS^G12V. KRAS^G12C is the most potent covalent target of ARS-853 across more than 2,700 cellular proteins and consistently find that this compound exerts no effects on cellular signaling or growth in non-KRAS^G12C cells at concentrations up to 10-fold higher than its KRAS^G12C potency. ARS-853 reacts only with the inactive (GDP-bound), but the not the active (GTP-bound), state of KRAS^[1]. ARS853 reduced KRAS-GTP levels and ERK phosphorylation in human embryonic kidney 293 (HEK293) or H358 cells engineered to express KRAS^G12C but not in those expressing KRAS^G12C/A59G. ARS853 traps KRAS^G12C in a GDP-bound conformation by lowering its affinity for nucleotide exchange factors^[2].

製品説明

ARS-853 is a selective, covalent KRAS(G12C) inhibitor that inhibits mutant KRAS-driven signaling by binding to the GDP-bound oncoprotein and preventing activation. ARS-853 also induces apoptosis.

in vitro

ARS-853 treatment of KRAS^G12C cells led to a dose-dependent and nearly complete inhibition of CRAF-RBD (RBD)-mediated pulldown of KRAS from lysates, with an IC50 of approximately 1 μmol/L. Treatment of H358 cells by ARS-853 resulted in a significant loss of KRAS–CRAF interactions. Consistent with an inactive state of KRAS^G12C once bound to ARS-853, downstream signaling through both MAPK (including pMEK, pERK, and pRSK) and PI3K signaling (pAKT) pathways was inhibited by ARS-853 in H358 and other KRAS^G12C cell lines. The inhibition of RAF-RBD pulldown and KRAS downstream signaling was sustained over a period of 72 hours, accompanied by G1 cell-cycle arrest, loss of Cyclin D1 and Rb expression, and an increase in the cell-cycle inhibitor p27 KIP1. In addition, hallmarks of apoptosis, including cleaved PARP and increases in sub-diploid DNA, were observed in H358 cells following treatment with ARS-853. No effects on RAF-RBD binding or downstream signaling were observed in A549 cells (KRASG12S), and the inhibitory effects of ARS-853 in H358 cells could be rescued by ectopic expression of KRAS^G12V. KRAS^G12C is the most potent covalent target of ARS-853 across more than 2,700 cellular proteins and consistently find that this compound exerts no effects on cellular signaling or growth in non-KRAS^G12C cells at concentrations up to 10-fold higher than its KRAS^G12C potency. ARS-853 reacts only with the inactive (GDP-bound), but the not the active (GTP-bound), state of KRAS^[1]. ARS853 reduced KRAS-GTP levels and ERK phosphorylation in human embryonic kidney 293 (HEK293) or H358 cells engineered to express KRAS^G12C but not in those expressing KRAS^G12C/A59G. ARS853 traps KRAS^G12C in a GDP-bound conformation by lowering its affinity for nucleotide exchange factors^[2].

プロトコル(参考用のみ)

細胞アッセイ	細胞株	H358 (G12C) cells
	濃度	0.05, 0.1, 0.5, 1, 5, 10, 50 μM
	反応時間	5 h
	実験の流れ	KRAS^G12C mutant cells (H358) were treated with ARS853 for 5 hours. The effect on the level of active, or GTP-bound, KRAS was determined by a RAS-binding domain pull-down (RBD:PD) assay and immunoblotting with a KRAS-specific antibody.

参考

Selleckの高級品が、幾つかの出版された研究調査結果（以下を含む）で使われた：

Real-time monitoring of the reaction of KRAS G12C mutant specific covalent inhibitor by in vitro and in-cell NMR spectroscopy [ Sci Rep, 2023, 10.1038/s41598-023-46623-w]	PubMed: 37935773
HDLBP promotes hepatocellular carcinoma proliferation and sorafenib resistance by suppressing Trim71-dependent RAF1 degradation [ Cell Mol Gastroenterol Hepatol, 2022, S2352-345X(22)00216-8]	PubMed: 36244648
Profiling oncogenic KRAS mutant drugs with a cell-based Lumit p-ERK immunoassay [ SLAS Discov, 2022, S2472-5552(22)12517-7]	PubMed: 35288294
Investigation of KRAS Dependency Bypass and Functional Characterization of All Possible KRAS Missense Variants [ ProQuest, 2020, N/A]	PubMed: None
Coxsackievirus Type B3 Is a Potent Oncolytic Virus against KRAS-Mutant Lung Adenocarcinoma. [ Mol Ther Oncolytics, 2019, 14:266-278]	PubMed: 31463367

長期の保管のために-20°Cの下で製品を保ってください。

人間や獣医の診断であるか治療的な使用のためにでない。

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